For most people, a yeast infection or case of thrush is little more than a nuisance. But for people with a compromised immune system, it can be deadly. New research from OMRF has solved the riddle of how the yeast invades cells to cause illness.
About 80 percent of humans live in harmony with Candida albicans, a fungus that grows in the mouth and gastrointestinal tract. For patients with weakened immune systems or those recovering from surgery or chemotherapy, the yeast can be a killer. According to the Centers for Disease Control, Candida is the fourth most common cause of bloodstream infections among U.S. hospital patients.
OMRF researchers Hao Wu, Ph.D. and Jordan Tang, Ph.D., have published a new paper in The Federation of American Societies for Experimental Biology (FASEB) Journal, which describes how C. albicans uses a Trojan horse mechanism to enter and kill cells.
Tang, who holds the J.G. Puterbaugh Chair in Medical Research at OMRF and whose career has included innovations in stomach digestion, AIDS and Alzheimer’s disease, said he became interested in the yeast because it does something familiar to his other areas of research—it uses a kind of chemical “scissors” called proteases. Proteases are a kind of enzyme that cut proteins and are used in everything from digestion to blood clotting and more.
“For years, researchers have assumed that the way yeast gets in human tissue is by using these scissors to cut outside proteins that glue the mucosal membrane cells together. Then, we thought the yeast could go through the resulting gap, which is what it must do to create a fungal infection called candidiasis,” he said.
The only problem with that theory is that those scissors only work in an acidic environment, while the mucosa is generally neutral, he said. So they began to look at the physical structure of C. albicans and found it had three long “arms” that are absent in other kinds of proteases. One of the arms turns out to contain a unique structure call RGD, which is used by our body to transport materials into the mucosal cells.
“We tracked the movement of these scissors and found that they ended up in some pouches inside of the cells called ‘lysosomes,’” Tang said.
Lysosomes are cells’ acidic stomachs, which provide a perfect environment to allow the yeast’s scissors to go to work, he said. The process causes lysosome membranes to leak and, after a couple of days, causes the cell to go through apoptosis—or programmed cell death. When mucosal cells die, it leaves big holes for Candida yeast to enter.
Just as the Trojan Horse was used to sneak past the defenses of Troy, these biological scissors are used by C. albicans to get inside and destroy the first line defense of the mucosa.
Now that they understand how the infection begins, Tang said there’s potential to create new drugs that use RGD to go inside where the yeast’s scissors are working. The drugs created from this new concept may assist the treatment alongside already existing antibiotics and anti-fungal medications to kill the yeast before it can cause serious illness.
Scientists who collaborated on the paper include Arun Ghosh, Ph.D., of Purdue University, Peter Staib, Ph.D., of the Hans Knoell Institute in Jena, Germany and Michel Monod, Ph.D., of the University Hospital of Lausanne, Switzerland.
